Submissions for variant NM_000249.4(MLH1):c.1420C>G (p.Arg474Gly)

dbSNP: rs147939838

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000767186	SCV000149369	uncertain significance	not provided	2023-05-31	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history including colon and breast cancer (Maxwell et al., 2015; Yehia et al., 2018); Published functional studies demonstrate no damaging effect in a cell survival assay (Bouvet et al., 2019); This variant is associated with the following publications: (PMID: 25503501, 29684080, 30998989, 22753075, 12697830, 29175432, 18561205)
Ambry Genetics	RCV000115460	SCV000184512	likely benign	Hereditary cancer-predisposing syndrome	2022-04-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV001081815	SCV000254348	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-21	criteria provided, single submitter	clinical testing
Counsyl	RCV000412185	SCV000488993	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2016-08-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000767186	SCV000601356	likely benign	not provided	2021-03-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115460	SCV000684743	likely benign	Hereditary cancer-predisposing syndrome	2023-03-22	criteria provided, single submitter	clinical testing
Mendelics	RCV000708924	SCV000838017	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000412185	SCV001136414	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2019-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115460	SCV002528649	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-10	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281934	SCV002571950	uncertain significance	not specified	2022-08-11	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1420C>G (p.Arg474Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251410 control chromosomes, predominantly at a frequency of 0.00092 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.29 fold of the estimated maximal expected allele frequency for a pathogenic variant in MLH1 causing Lynch Syndrome phenotype (0.00071), suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1420C>G has been reported in the literature in individuals affected with breast cancer, who were BRCA1/2-negative, but without other strong evidence for causality (Maxwell_2014). This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. A functional study which measured MMR activity in response to a DNA damaging agent in a human colorectal cancer cell line reported the variant as non-damaging (Bouvet_ 2019). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Seven submitters classified the variant as VUS while two classified as likely benign. Based on the evidence outlined above, the variant was classified as VUS - possibly benign.
Myriad Genetics, Inc.	RCV000412185	SCV004018144	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-14	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000412185	SCV004171407	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-11-13	criteria provided, single submitter	clinical testing	The MLH1 c.1420C>G (p.Arg474Gly) missense change has a maximum subpopulation frequency of 0.08% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, however functional studies suggest that this variant does not affect MLH1 function (PMID: 30998989). To our knowledge, this variant has not been reported in individuals with Lynch syndrome or constitutional mismatch repair deficiency syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.